Chromans

ABSTRACT

Des-N-methyldihydroacronycine and analogs thereof and a process for the preparation thereof comprising (1) halogenating a 7alkoxy-2,2-dialkylchroman to the 6-halo derivative, (2) converting the b-halo derivative to the 5-amino-substituted chroman with sodium amide in liquid ammonia, (3) condensing the amine with an o-halobenzoic acid to yield the 2-carboxyanilino derivative and (4) cyclizing the carboxyanilino compound to the des-N-methyldihydroacronycine with polyphosphoric acid. Des-Nmethyldihydroacronycine can be converted to acronycine, a known antitumor agent.

Q United States Patent [111 5 [72] Inventors Russell Kwolr; [56]References Cited [21 l A I N mgohland, both of Indianapolis, In OTHERREFERENCES o. [22] fi, My 5, 1968 Chatter ea et 31., Ber., vol. 96,2356- 61 (1963) [4S] Patented Nov. 16, 1971 Primary Examiner-John M.Ford [73] Assignee Eli Lilly and Company Altomeys-Everet F. Smith andWalter E. Buting Indianapolis, Ind.

' 541 CHROMANS [50] FieldolSearch 260/3452 ABSTRACT:Des-N-methyldihydroacronycine and analogs thereof and a process for thepreparation thereof comprising (i) halogenating a 7-alkoxy-2,2-dialkylchroman to the 6-halo derivative (2) converting theb-halo derivative to the 5- amino-substituted chroman with sodium amidein liquid ammonia. (3) condensing the amine with an o-halobenzoic acidto yield the 2-carboxyanilino derivative and (4) cyclizing thecarboxyanilino compound to the des-N-methyldihydroacronycine withpolyphosphoric acid. Des-N-methyldihydroacronycine can be converted toacronycine, a known antitumor agent.

CHROMANS BACKGROUND OF THE INVENTION Acronycine was first isolated fromAcronychia baueri by Lahey and coworkers [Nature, 162, 223 (1948) andAust. J. Sci. Res, A2, 423 (l949)]. In 1966, MacDonald and Robertson,Aust. J. Chem., I9, 275 (1966), and Govindachari, Pai, and Subramaniam,Tetrahedron, 22, 3245 (1966) determined that acronycine has thefollowing structure: 1

wherein R is methoxy and R is methyl.

In addition, Govindachari et al. isolated noracronycine which differsfrom acronycine in that R in the above formula is hydroxy;des-N-methylacronycine, in which R is hydrogen; anddes-N-methylnoracronycine, in which R is hydroxy and R is hydrogen.

The synthesis of acronycine from noracronycine is described in Aust. J.Sci. Res., A2, 622 (I949).

Recently, it was found by Svoboda and coworkers [J. Pharm. Sci, 55, 758(1966) and Lloydia, 29, 206 (1966)] that acronycine has an extremelypowerful antitumor action against transplanted tumors in mice,particularly against Shionogi carcinoma, C-l498 myelogenous leukemia,Mecca lymphosarcoma, and X-5563 plasma cell myeloma.

SUMMARY wherein R and R are hydrogen or C,C alkyl, R is C C. alkoxy orbenzyloxy, R is hydrogen, C C alkyl, C -C alkoxy, fluoro, chloro, bromo,nitro or trifluorornethyl. The term C,- C alkyl" as employed herein isintended to include both straight and branched chained alkyl groups, asfor example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl and tertbutyl. The term C -C, alkoxy" as used herein isintended to include both the straight and branched chained alkyl groups,defined above, attached to an oxygen atom, as for example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy andtert-butoxy.

The novel process of this invention proceeds through a reaction sequencewhich involves, initially, the halogenation of a7-alkoxy-2,Z-dialkylchroman to yield the corresponding 6-halo-chroman.Amination of the 6-halo-7-alkoxy-2,2-dialkylchroman with an alkali metalamide in liquid ammonia affords the 5-amino-7-alkoxy-2,2-dialkylchroman,rather than the expected 6-amino compound. Condensation of the 5-aminochroman with an o-halobenzoic acid under the conditions of theJourdan-Ullmann reaction yields a5-(2-carboxyanilino)-7-alkoxy-2,2-dialkylchroman. The latter compound,when heated in the presence of polyphosphoric acid, un-

dergoes an intramolecular cyclization to form the desired des-N-methyldihydroacronycine.

When the starting material in the present process is 7-methoxy-2,2-dimethylchroman, halogenau'on and amination 5 yield5-amino-7-methoxy-2,2-dimethylchroman. Condensation of this aminederivative with an o-halobenzoic acid, followed by cyclization is thepresence of polyphosphoric acid yields des-N-methyldihydroacronycine.

DETAILED DESCRIPTION The starting material for the synthesis of thecompounds of this invention is a 7-alkoxy-2,2-dialkylchroman representedby the formula substituted acrylic acid to yield a substitutedchromanone of the fonnula R2 0 HO- wherein R and R have the same meaningas hereinabove.

Etherification by any of the methods commonly used for the formation ofphenolic ethers yields the corresponding7-alkoxy-2,2-dialkyl-4-chromanone. For example, the 7-hydroxy-4-chromanone is reacted with an alkyl halide such as methyl iodide or abenzyl halide such as benzyl chloride in the presence of potassiumcarbonate in a refluxing solvent such as acetone to yield thecorresponding ether of the 4- chromanone. Etherification of the7-hydroxy-4-chromanone can also be effected by reaction with adiazoalkane such as diazomethane or diazoethane in a suitable solvent.Still another method of etherifying the 4-chromanone involves thereaction of the phenol with a dialkyl ester of sulfuric acid in thepresence of sodium hydroxide.

The 7-alkoxy-2,2-dialkyl-4-chromanone thus prepared is converted intothe corresponding chroman by either of two methods. In the first ofthese, the 4-chromanone is reduced with lithium aluminum hydride inrefluxing ether to yield the corresponding 4-chromanol. The 4-chromanolis dehydrated in the presence of phosphorus oxychloride and pyridine inrefluxing benzene to yield a 7-alkoxy-2,2-dialkyl-2H- chromene.Catalytic hydrogenation of the chromene affords the chroman. Thehydrogenation can be carried out in ethanol under a hydrogen pressure of40 p.s.i.g. at room temperature in the presence of Raney nickel.

Alternatively, the chroman can be prepared from the7-alkoxy-2,2-dialkyl4-chromanone directly by high-pressure,high-temperature hydrogenation in the presence of a copper chromitecatalyst. The hydrogenation can be carried out in a high-pressurerocking autoclave under a hydrogen pressure of about 2,000 to about4,000 p.s.i.g. at a temperature of about 200 to about 300 C. Under theseconditions if temperature and pressure, the reduction proceeds to yieldthe chroman within three hours. The hydrogenation is convenientlycarried out without a solvent if desired; however, solvents such asdioxane and ethanol, which are compatible with the copper chromitecatalyst and the conditions of the hydrogenation, can be used. Thehigh-pressure technique and the copper chromite catalyst employed in theabove one-step reduction are described by Homer B. Adkins, Reaction ofHydrogen with Organic Compounds over Copper Chromium Oxide and NickelCatalysts. University of Wisconsin Press, l937.

It should be noted that the one-step high-pressure method of preparingthe chroman cannot be employed when R is benzyloxy, since thehydrogenation conditions described would result in Odebenzylation in the7'position.

As previously noted, the first step in the present process for thesynthesis of des-N-methyldihydroacronycine and analogs thereof involvesthe halogenation of a chroman (l) to yield a o-halochroman (ll).

In the above formulas, R, R and R have the same meaning as hereinaboveand X is chloro or bromo. The halogenation is preferably carried outwith chlorine or bromine at a reaction temperature between about -5 andabout 30 C. in the presence of an inert solvent such as chloroform,ethylene dichloride, carbon tetrachloride or the like. When chlorine isthe halogenating agent, chlorine gas is allowed to bubble slowly througha solution of the chroman at room tempera ture. When bromine is thehalogenating agent, a solution of bromine in one of the indicatedsolvents is added dropwise to a solution of the chroman, preferably inthe same solvent. In a preferred embodiment, a carbon tetrachloridesolution of bromine is cooled to C. and added slowly by dropwiseaddition to a cooled (0 C.) carbon tetrachloride solution of thechroman. The reaction mixture is thereafter allowed to warm to roomtemperature, and the product is isolated according to procedures knownin the art. The product is generally purified by distillation.

The 6-halochroman thus obtained is caused to react with an alkali metalamide in liquid ammonia. The 6-halo substituent is lost, aminationoccuring in the -position to yield a 5- aminochroman according to thefollowing reaction scheme:

11 III wherein R, R, R and X have the same meaning as hereinabove.Sodium amide and potassium amide in liquid ammonia are particularlyeffective aminating agents. A preferred method of preparing theS-aminochroman involves reacting sodium amide with the 6-halochroman inliquid ammonia to yield the 5-amino compound as the sole aminatedproduct. The amination is customarily carried out at a reactiontemperature between about 75 and 33 C. and is usually complete at theend of 3 to 4 hours.

The amination method described above is especially advantageous in thepresent process, since alternate methods for the introduction of theamino substituent into the chroman nucleus produce position isomerswhich are not suitable for the preparation ofdes-N-methyldihydroacronycine.

The S-aminochromans and the pharmaceutically acceptable nontoxic saltsthereof, in addition to being useful as intermediates in the synthesisof acronycine and its analogs, are also useful as mild central nervoussystem depressants in warm-blooded animals.

The novel 6-chloroarid o-bromochromans of this invention areparticularly valuable as synthetic percursors of the 5- aminochromans.As such they are key intermediates in the present novel process for thesynthesis of acronycine and its analogs.

Reaction of the S-aminochroman (ill) under the conditions of theJourdan-Ullmann Reaction with an ortho-halobenzoic acid in the presenceof copper powder yields the 5-( 2-carboxyanilino)chroman of the formulaC O OH vention to yield the corresponding 5-(2-carboxyanilino)chromans.

The preparation of the desired 5-(2-carboxyanilino)chroman is preferablycarried out in an inert solvent. Ethers such as diethyl ether, dipropylether, dioxane, tetrahydrofuran and the like, alcohols such as methanol,ethanol, n-butanol, n-amyl alcohol, isoamyl alcohol and the like andother inert solvents commonly used in the Ullmann reaction can beemployed in the present description. The reaction temperature employedin the present description. The reaction temperature employed isconveniently the reflux temperature of the solvent. Some form of finelydivided copper or cuprous salt is employed as a catalyst and a hydrogenhalide acceptor is also desirably added to the reaction mixture for bestresults. The reaction conditions for the Ullmann reaction are describedin greater detail by R. M. Acheson, Acridines, The Chemistry ofHeterocyclic Compounds, lnterscience Publishers, lnc., New York, 1956.

A preferred method for the preparation of the 5-(Z-carboxyanilino)chroman (lV) utilizes n-amyl alcohol as the solvent,and is carried out at reflux temperature in the presence of spongycopper, with excess potassium carbonate as the hydrogen halide acceptor.Small amounts of eupric carbonate added to the reaction mixture appearto enhance the yield of the 5( 2-carboxyanilino)chroman. The reaction isadvantageously conducted for about 48 hours, although satisfactoryyields may be obtained with longer or shorter reaction times.

The 5-(2-carboxyanilino)chroman is separated from the reaction mixtureby conventional isolation techniques and is advantageously used in thenext step of the reaction sequence without further purification.

The 5-(2-carboxyanilino)chroman undergoes an intramolecular cyclizationto yield a pyranoacridinone as illustrated in the following equation:

' pyrano[ 2,3-C acridinone.

When R and R are methyl, R is methoxy and R is hydrogen, the compound offormula V is des-N-methyldihydroacronycine, which can be converted toacronycine as follows: Des-N-methyl-dihydroacronycine is alkylated byreaction with methyl iodide in refluxing acetone in the presence ofanhydrous potassium carbonate to yield dihydroacronycine as described byR. D. Brown and coworkers, Australian J. Sci. Research, A2, 622 (1949).O- demethylation at the 6-position of dihydrocaronycine by heating thehydrochloride salt of dihydroacronycine produces nordihydroacronycine.The reaction of nordihydroacronycine with2,3-dichloro-5,o-dicyanoquinone (DDQ) in refluxing toluene yieldsnoracronycine as described in the copending application of J. R. Beckand A. Pohland, Ser. No. 653,667, filed July 17, 1967. Treatment ofnoracronycine with dimethyl sulfate in refluxing acetone effectsO-methylation of the 6- hydroxyl group to yield acronycine.

When R and R are groups other than methyl, or when R is a group otherthan methoxyl, or when R is a group other than hydrogen, compound V canbe converted by the same sequence of reactions into the correspondinganalogs of acronycine. The process of the present invention thusprovides a useful method for the preparation of analogs of the knownantitumor agent acronycine, as well as of acronycine itself.

The novel 5-(2-carboxyanilino)chromans are useful intermediates for thesynthesis of the pyranoacridinones in the instant process. Thepyranoacridinones, represented by formula V, in addition to theirutility in the synthesis of acronycine and its analogs are also usefulintermediates for the preparation of anthraquinone vat dyes. Forexample, the pyranoacridinones can be condensed with phthalic anhydrideunder mild Friedel- Crafts conditions to yield the 2-carboxybenzoylderivatives, which can be cyclized in the presence of an acid catalyst,such as sulfuric acid or polyphosphoric acid, to the acridinonesubstituted anthraquinone.

The following illustrative examples describe more fully the 1 practiceof the present invention.

PREPARATION OF STARTING MATERIALS 7-Methoxy-2,2-dimethyl-4 chromanone.One

under reflux for four hours with 150 ml. of metliyliodide in one literof acetone in the presence of 75 g. of anhydrous potassium carbonate.The reaction product mixture was filtered and the filtrate wasevaporated in vacuo to remove the solvent and yield a residue containing7-methoxy-2,2- dimethyl-4-chromanone formed in the reaction. The residuewas extracted with l,000 ml. of ether, and the extract was washed with250 ml. of 2N sodium hydroxide and with water. The extract was dried andevaporated in vacuo to yield crystalline7-methoxy-2,2dimethyl-4-chromanone, melting at about 82 C. afterrecrystallization from hexane.

Analysis-Calculated: C, 69,88; H, 6.84

Found: C, 70,08; H, 6.94

Method A 7-Methoxy-2,2-dimethyl-2H-chromene. A solution of grams of7-methoxy-2,2-dimethyl-4-chromanone in one liter of anhydrous ether wasadded slowly to a stirred mixture of 26 g. of lithium aluminum hydrideand 500 ml. of anhydrous ether and the reaction mixture was refluxedovernight. The reaction product mixture was cooled, ethyl acetate wascautiously added until hydrogen evolution ceased, and then 500 ml. ofwater were slowly added. The ether layer was separated and dried, andthe ether was evaporated in vacuo to yield 85 g. of7-methoxy-2,2-dimethyl-4-chromanol as a viscous oil. The 4-chromanol soobtained was dissolved in 500 ml. of benzene and the solution was addedto a mixture of 42 ml. of phosphorus oxychloride, 250 ml. of pyridine,and 300 ml. of benzene. The reaction mixture was stirred and heated at atemperature of about 85 C. for l hour, poured into ice water andextracted with 800 ml. of ether. The extract was washed successivelywith 200 ml. of 6N hydrochloric acid, 500 ml. of a [0 percent solutionof sodium bicarbonate, and water. The washed extract was dried andevaporated in vacuo to yield 67 g. of 7-methoxy-2,2-dimethyl-2H-chromeneas a colorless oil; b.p. 85-88 C. at 0.5 mm. Hg; N 1.5541.

Analysis-Calculated: C, 75,76; H, 7.42

Found: C, 75.97; H, 7.37

7-Methoxy-2,Z-dimethylchroman. Forty-eight grams of 7-methoxy-2,2-dimethyl-2H-chromene were dissolved in 150 ml. of ethanoland hydrogenated over 10 g. of Raney nickel catalyst under an initialhydrogen pressure of 50 p.s.i. at a temperature of about 25 C. Hydrogenuptake was complete in 1 hour. The catalyst was removed by filtrationand the filtrate was evaporated in vacuo to yield 7-methoxy-2,2-dimethylchroman as an oil. Vacuum distillation of the oil yielded 40 g.of purified material; b.p. 72 C. at 0.3 mm. Hg.

Method B 7-Methoxy-2,2-dimethylchroman. Eighty grams of 7-methoxy-Z,2dimethyl-4-chromanone and 35 g. of copper chromitehydrogenation catalyst were placed in a 500 ml. high-pressure rockingautoclave which was pressurized to 3,000 p.s.i. with hydrogen gas afiercharging. The autoclave and contents were heated to 200 C. andmaintained at that temperature for 45 minutes with continuous agitation.The autoclave was allowed to cool to room temperature, vented, anddismantled. The crude product and catalyst were washed from theautoclave with 200 ml. of ethanol. The catalyst was removed byfiltration and the ethanol was removed from the filtrate by evaporationunder reduced pressure. The residue was distilled in vacuo to yield 50g. of purified 7-methoxy-2,2- dimethylchroman, b.p. 72 C./O.3 mm. Hg; N1.5312.

Analysis-Calculated: C, 74.96; H, 8.38

Found: C, 75.07; H, 8.40

EXAMPLE I Preparation of 6-bromo-7-methoxy-2,Z-dimethylchroman.

A solution of 20.8 g. of bromine in ml. of carbon tetrachloride wasslowly added at a temperature of about 0 C. to a stirred solution of 25g. of 7-methoxy-2,2- dimethylchroman in 200 ml. of carbon tetrachloride.The reaction mixture was allowed to stand at a temperature of 25 C. for1 hour, afier which it was washed with 200 ml. of a 20 percent solutionof sodium bicarbonate in water. The washed reaction mixture was driedand evaporated in vacuo to yield an oil. Vacuum distillation of the oilyielded 33 g. of 6-bromo- 7-methoxy-2,Z-dimethylchroman, b.p. l40 C. at0.3 mm. Hg. The distilled oil solidified on standing and melted at about39-4l C.

Analysis-Calculated: Br, 29.47

Found: Br, 29.74

Preparation of S-amino-7-methoxy2,Z-dimethylchroman.

6-Bromo-7-methoxy-2,Z-dimethylchroman (75.4 g.) was stirred for fourhours with 25 g. of sodium amide in 750 ml. of liquid ammonia. Solidammonium chloride (34 g.) was added portionwise to the reaction productmixture to decompose the sodium amide, and the ammonia was allowed toevaporate. One liter of benzene was added to the residue and evaporatedin vacuo to remove residual ammonia. The residue was extracted with oneliter of ether, and the extract was treated with gaseous hydrogenchloride to precipitate the hydrochloride ofS-amino-7-methoxy-2,Z-dimethylchroman. The precipitated salt wasfiltered off and recrystallized from ethanol-ether to yield 40 g. ofcolorless crystals melting at about 255-258 C.

' The salt was reacted with aqueous sodium hydroxide to obtain-amino-7-methoxy-2,2-dimethylchroman as the free base melting at 6768 C.after recrystallization from hexane.

Analysis-Calculated: N, 6.76

Found: N, 6.98

Preparation of des-N-methyldihydroacronycine A mixture of 38 g. of5-amino-7-methoxy-2,2- dimethylchroman, 38 g. of o-iodobenzoic acid, l3g. of potassium carbonate, 9 g. of spongy copper, and 3.2 g. of coppercarbonate in one liter of n-amyl alcohol was refluxed with stirring for48 hours. The reaction product mixture was cooled and diluted with 200ml. of water, and the n-amyl alcohol was removed by steam distillation.The remaining mixture was filtered while hot, cooled, and washed withether to remove unreacted starting material. The aqueous mixture wasacidified with l50 ml. of 6N hydrochloric acid and extracted with 600ml. of chloroform. The chloroform extract was dried and evaporated invacuo to yield crude 5-(2-carboxyanilino)-7- methoxy-2,2-dimethylchromanas a brown residue which was heated with 100 ml. of polyphosphoric acidfor 2 hours at a temperature of about 90 C. and then poured into crushedice. The resulting yellow solid was filtered off and washed with water.The crude product, des-N-methyldihydroacronycine, was recrystallizedthree times from acetone to yield 3.5 g. of pale yellow crystals meltingat about 297-299 C.

Analysis-Calculated: C, 73.77; H, 6.19; N, 4.53

Found: C, 74.06; H, 6.19; N, 4.57

infrared, ultraviolet and nuclear magnetic resonance spectra were inagreement with the proposed structure.

EXAMPLE I] Following the reaction procedure of example 1, reaction of7-ethoxy-2-ethyl-2-methylchroman with bromine affords 6-bromo-7-ethoxy-2-ethyl-2-methylchroman. Amination of the 6-bromoderivative with sodium amide in liquid ammonia yields5-amino-7-ethoxy-2-ethyl-2-methylchroman which, on condensation with2-bromo-5-nitrobenzoic acid, yields 5-(4-nitro-a-carboxyanilino)-7-ethoxy-2-ethyl-2-methylchroman. Heating theanilino derivative in the presence of polyphosphoric acid affords6-ethoxy-3-ethyl-3-methyl-2,3- dihydrol0-nitro-7( 12H l H-pyrano[2,3-C1acridinone.

EXAMPLE Ill Following the reaction procedures of example i, reaction of7-methoxy-2,2-diethylchroman with bromine yields 6-bromo-7-methoxy-2,2-diethylchroman. Amination of the 6-bromo derivative withsodium amide in liquid ammonia afiords 5-amino-7-methoxy-2,2-diethylchroman which, on condensation with5-chloro-2-isodobenzoic acid yields 5-(4-chloro-2-carboxyanilino)-7-methoxy-2,Z-diethylchroman. Heating the anilinoderivative in the presence of polyphosphoric acid yields@methoxyl0chloro-3,3-diethyl-2,3-dihydro-7( 12H lH-pyrano[2,3-C1acridinone.

We claim: 1. A compound of the formula wherein R and R are hydrogen or(l -C, alltyl, IR is C C alkoxy or benzyloxy, X is hydrogen, chloro orbromo, Z is hydrogen, amino or Ser. No. 742,48!

OOH

wherein R is a substituent in the 4 or 5 position and is hydrogen, C C,alkyl, C,-C., alkoxy, fluoro, chloro, bromo, nitro or trifluoromethyl,such that when 2 is hydrogen, X is chloro or bromo, and when X ishydrogen, Z is amino or with the limitation that one of X or Z must behydrogen.

1? t a I]! I3

